Anti-Factor D Antibody Variants and Uses Thereof

Abstract

The invention relates to anti-Factor D antibody variants, their production and their use in the preparation of compositions and medicaments for treatment of diseases and disorders associated with excessive or uncontrolled complement activation.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional application No. 61 / 987,298, filed May 1, 2014, and U.S. Provisional Application No. 62 / 076,372, filed Nov. 6, 2014, which are incorporated herein by reference in their entirety.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Apr. 27, 2015, is named P05826-US_SL.txt and is 30,764 bytes in size.BACKGROUND OF THE INVENTION[0003]The development of therapeutic antibodies represents a revolutionary era in the long history of human medicine. More than 30 antibodies have been approved for human therapy, and over 250 antibodies are in clinical development worldwide for a wide range of major diseases, including cancer, autoimmunity, inflammation, cardiovascular disease, infectious diseases and ocular disease. Over the past decade, t...

AI Technical Summary

Benefits of technology

The present invention is about improving the stability and potency of an anti-factor D antibody. It explains that by making specific changes to the amino acid residues in the antibody, its stability can be increased without losing its ability to bind to factor D. These changes include replacing aspartic acid residues with glutamic acid, adding or replacing serine or asparagine residues with other amino acids to reduce deamidation, and increasing the overall negative charges of the antibody by replacing aspartic acid with serine or glutamic acid. The goal of the invention is to create a more stable and effective anti-factor D antibody for use in therapy.

Problems solved by technology

Successful development and viable use of antibody therapeutics pose many unique challenges comparing to traditional medicines that are small organic and inorganic molecules.

Meanwhile, certain routes of administration are associated with limitations such as delivery time, volume and physical force that require the high dose protein to be in a high-concentration formulation (e.g., at least 100 mg / ml).

However, highly concentrated protein formulations pose particular challenges with respect to stability, solubility, viscosity and other protein properties.

Proteins can be unstable and become degraded via multiple physical and chemical degradation pathways.

Antibody instability is undesirable for drug development, as it can lead to decreased amount of active drug and lower in vivo efficacy, increased variability among batches of the therapeutics, and perhaps most importantly, immunogenicity in patients against aggregates and degradants.

Antibodies are large multidomain proteins, and factors contributing to their stability and propensity to aggregate are complex, including many extrinsic conditions such as temperature, pH, concentration, ionic strength and physical stress.

Late forms of the disease are the leading cause of vision loss in industrialized countries.

Advanced dry AMD can result in significant retinal damage, including geographic atrophy (GA), with irreversible vision loss.

Moreover, patients with dry AMD can progress to the wet form, in which abnormal blood vessels called choroidal neovascular membranes (CNVMs) develop under the retina, leak fluid and blood, and ultimately cause a blinding disciform scar in and under the retina.

Eyes have many unique biophysical and anatomic features that make the ocular drug delivery more challenging.

For example, blood-ocular barriers are defense mechanisms for protect the eye from infection, but at the same time make it hard for drug to penetrate, especially for diseases in the posterior segments of the eye.

Implants are produced using a hot-melt extrusion process such that the drug is briefly exposed to temperatures approaching 90° C. Although the drug remains in solid state for the duration of release, degradation of PLGA may expose the drug to a low pH environment.

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